Process for the preparation of morphinane  analogues

ABSTRACT

The present invention relates to an improved process for preparing morphinane analogues of formula 1 
     
       
         
         
             
             
         
       
     
     wherein the substituents R 1 , R 2 , R 2a , R 3 , R 4 , R 5  and Y have the meanings as defined in the specifications.

FIELD OF INVENTION

This present invention relates to a novel, improved process for thesynthesis of certain morphinane analogues.

BACKGROUND OF THE INVENTION

The present invention relates to a novel process for preparation ofmorphinane analogues i.e compounds of formula I. The morphinanes may becharacterised by a common chemical structure that of a cyclic tertiaryamine represented by following structure:

These analogues exert their effect at the opioid receptors in thecentral nervous system and other tissues and are useful aspharmaceutical substances for treatment of pain, drug abuse and variousother disorders. Because of the high potency and diverse uses of themorphinane derivatives in therapy for human as well as for veterinaryuse, there is an increasing demand for medicinal morphinanes. Some ofthe morphinane analogues known in the art are as follows:

The prior known processes for preparation of the morphinane analoguesgenerally begin with thebaine or its O-demethylated derivative,oripavine. Thebaine occurs naturally in plant sources from which it isextracted and purified by an expensive and laborious procedure.Thebaine-producing plants require special agronomical and environmentconditions which can further increase the final cost of thebaineextracted thereform. Consequently, there is a need for a process ofpreparation of morphinane derivatives which gives high yields of qualityproducts and which uses safer solvents and reagents.

The process for the preparation of morphinane derivatives comprisesmainly of two steps starting from thebaine or oripavine namely the.N-demethylation and N-alkylation. The following patent referencesgeneralize the state of art for the N-dealkylation of thebaine ororipavine.

U.S. Pat. No. 3,433,791 (as referred to as '791) discloses endoethanonorthebaine and nororipavine derivatives, including,N-cyclopropylmethyl-6,14-endoethano-7-(2-hydroxy-2-methyl-2-tertbutyl)-tetrahydronororipavinecommonly known as Buprenorphine. The '791 patent describesN-demethylation of endoethano thebaine and oripavine derivatives in atwo step process, first step involving formation of N-cyano derivativeusing cyanogen bromide followed by hydrolysis of the N-cyano derivativeto yield the N-demethylated product. The process gives a lower yield(˜70%) of the N-demethylated product and further requires the use ofcyanogen bromide, which is toxic and requires great precautions for usein large scale. The following scheme 1 outlines the process ofpreparation of buprenorphine as disclosed in the '791 patent.

Canadian Patent No. 2597350, discloses preparation of noroxymorphonederivatives like naltrexone and naloxone. It discloses N-demethylationof noroxymorphone using ethyl chloroformate in presence of basicconditions to prepare noroxymorphone carbamate which is hydrolyzed toform the N-demethylated derivative. More specifically, it describes theN-demethylation of diacetyloxymorphone to form diacetyloxymorphonecarbamate, which is then hydrogenated to yield noroxymorphone i.e. theN-demethylated derivative. The yield of the N-demethylated product is˜65% based on the starting material used. Further, European Patent No.164290 discloses a similar process for preparation of14-hydroxymorphinanes with lower yields. It was found by us that withthe use of ethylchloroformate for N-demethylation of compounds offormula I of the present invention, the reaction did not go tocompletion and the yields obtained were lower.

Also, U.S. Pat. No. 4,141,897 discloses use of vinyl chloroformate forN-demethylation of N-alkyl-14-hydroxymorphinans, however, the processsuffers from disadvantages in that the yield obtained is 70-85%, theinstability of the reagent leads to variable output and its delicatepreparation requires high cost.

The process of present invention does not use toxic reagents likecyanogen bromide for N-demethylation, instead uses anC₁₋₄alkylchloroformate along with an alkali iodide and a heterogenousbase, for the N-demethylation of thebaine or oripavine derivatives. Theprocess gave higher yields, which is near the theoretically calculatedvalue, of the N-demethylated derivative with good purity. The use ofalkali iodide along with an C₁₋₄alkylchloroformate and a base, accordingto the present invention, has not been disclosed heretobefore forN-demethylation of the morphinane analogues.

Further, N-alkylation of the morphinane analogues is described inseveral references, for example, U.S. Pat. No. 3,332,950 (referred to as'950 hereinafter), which discloses 14-hydroxydihydronormorhinones,specifically, naltrexone and methods of preparing the same. The '950patent discloses two methods for N-alkylation of morphinane derivativesdisclosed therein. In one of the methods, N-alkylation is carried out ina two-step reaction. The first step involves use of cyclopropylcarbonylchloride to obtain a carbonylalkyl substituted compound which wassubjected to reduction using lithium aluminium hydride (LiAlH₄), in thesecond step to generate the N-alkylated compound. The method isdisadvantageous in that it involves a two-step reaction forN-alkylation, uses highly reactive, pyrophoric metal hydride reagentlike LiAlH₄ and affords yield of approximately 33% starting fromnoroxymorphone. In another method (Scheme 2)14-hydroxydihydronormorphinone is treated with cyclopropylmethyl bromidein DMF to prepare naltrexone. The method employs high temperatures andprolonged reaction time (7 days) yet achieves only a 60% of theoreticalyield.

British Patent No. 1119270 discloses 14-hydroxydihydronormorphinederivatives such as Nalbuphine. In one of the methods disclosed therein,cyclobutylmethyl bromide is employed for N-alkylation. A similar processfor preparation of buprenorphine, Naloxone and Nalorphine has beendisclosed in the '791 patent, British Patent No. 939287 and U.S. Pat.No. 2,364,833, respectively, wherein the corresponding alkylhalide hasbeen used for N-alkylation of morphinane derivatives. We have found thatwhen the N-alkylation reaction using corresponding alkyl orcycloalkylbromide is not a clean reaction, the reaction is slow, doesnot go to completion and leads to an impure product. It was surprisinglyfound by us that the use of the corresponding alkanol, a C₁₋₃alkylsulfonylhalide and an alkali metal halide, in a single-step, forN-alkylation, hitherto not reported in literature for morphinaneanalogues, led the reaction to completion with corresponding increase inyield and quality of the product.

In addition to the N-demethylation and N-alkylation reactions, theprocess of preparation of a morphinane analogue, namely buprenorphine,starting from thebaine, comprises reactions for introducing endoethanobridge at the 6- & 14-position, addition of a tertiary butyl group tothe carbonyl of 7-acetyl group via grignard reaction and O-demethylationreaction (See Scheme I above). The process as generically disclosed forthe endoethano compounds in the '791 patent comprises reaction ofthebaine with methyl vinyl ketone to form the 7-acetylendoethenocompound via a 4+2 reaction, hydrogenation of the carbon-carbon doublebond of the endoetheno bridge using high hydrogen pressure, addition ofa tertiary butyl group to the carbonyl of 7-acetyl group via a grignardreaction employing benzene or diethylether or a combination of these asa solvent and O-methylation reaction which is carried out at atemperature of >200° C. in presence of an alkali. Also U.S. Pat. No.5,849,915 which discloses certain buprenorphine analogues, preparesendoetheno derivatives of morphinanes by reacting thebaine with methylvinyl ketone in a molar ratio of about 1:1746.

The process as disclosed in the '791 and the '915 patent for preparationof buprenorphine or its precursors suffers from disadvantages, in thatthe process is low yielding, for example, in the '791 patent the yieldsof the product obtained at each step is in the range of 25-70% with theoverall yield of only 4.5%. The prior art process for preparation ofendoethano compounds as disclosed in the '915 patent uses a large excessof methylvinyl ketone which is not only expensive but also islachrymatic in nature, which causes inconvenience in large scalesynthesis. The hydrogenation step, as disclosed above, uses highhydrogen pressure ˜58 psi furnishing yield of only ˜60%. The grignardreaction employs a combination of benzene and diethylether as solvent,which not only gives a low yield on ˜25%, but is also not advisablebecause of known carcinogenicity of benzene. Further, theO-demethylation reaction requires harsh environment i.e. hightemperatures in presence of an alkali which may cause an irreversibledamage to the phenolic moiety as observed in poor yield, obtained forthis reaction.

The process of the present invention is advantageous in that it uses ofmethylvinylketone in a quantity which is only four times the molarquantity of thebaine, yet furnishes a high yield of ˜90%. Further, thehydrogenation reaction is carried out at atmospheric pressure in 10%aqueous acetic acid, furnishing ˜83.0% yield. The grignard reaction ofthe 7-acetylated derivative, according to the present invention, avoidsthe toxic solvents like benzene, and instead uses solvents liketetrahydrofuran or diethylether or mixtures thereof, which arerelatively safer with a 3-fold improvement in yield of the product.Further, the process uses thiols for the O-demethylation reaction andrequires use of less harsher conditions of temperature, leading to afurther improvement in yield.

In summary, the state of art for synthesis of morphinane analogs usesreagents and solvents which are not eco-friendly. The synthesis of theanalogues involves several steps with low yields at several stages.Further the use of hazardous solvents, high pressure and hightemperature reactions, prolonged reactions, contribute to the cost ofproduction, inconsistent quality and requirement of large excess ofexpensive and controlled starting materials like thebaine. Thus, eventhough, the prior art discloses several processes for the preparation ofmorphinane derivatives, they have largely been unsuccessful in providinga process with high yield with safer reagents and solvents. The presentinvention involves steps furnishing high yields, employs stoichiometricquantities of reagents and uses class-2 and class-3 solvents which arerelatively innocuous. The process of the present invention utilizesmoderate reaction conditions, has reduced reaction time and furnisheshigh quality of the end products, all of which contribute significantlytowards making the process economical. Furthermore, the process usesstable reagents and produces reproducible results.

DESCRIPTION OF THE INVENTION

The present invention relates to novel process for preparation ofcompounds of formula 1 or salts thereof

wherein,R₁ is hydrogen;R₂ and R_(2a) are independently selected from hydrogen, hydroxy ormethoxy;or R₂ and R_(2a) together represent ═O or ═CH₂;R₃ is selected from hydrogen or a group of the formula A

wherein R₈ is selected from methyl or t-butyl;or R₂ and R₃ together may form, together with the carbon atoms to whichthey are attached a group of the formula B

R₄, when present, is in beta conformation and is selected from hydrogen,hydroxy;R₅ is selected from C₃₋₈ alkyl, alkenyl, alkynyl, cycloalkylalkyl,arylalkyl, alkoxyalkyl;Y is ethano or ethenothe dotted lines ------ indicate an optional single bond;with a proviso that when Y is present, R₄ and R_(2a) are absent and whenR₂ and R₃ together with the carbon atoms to which they are attached forma group of formula B, R_(2a) is absent.which comprises the steps of:(a) reacting a compound of formula 2

wherein,R′₂ and R′_(2a) are selected from hydrogen, methoxy or —O—R′, wherein R′is an oxygen protecting group,or R′₂ and R′_(2a) together represent ═O or ═CH₂;R₆ is methyl,R₇ is methyl or an oxygen protected group,R″₄ when present, is in beta conformation and is selected from hydrogenor an —O—R′ wherein R′ is an oxygen protecting groupR₃, Y and the dotted lines ------ have the meaning as defined above informula 1; with C₁₋₄alkylchloroformate, wherein the alkyl group isunsubstituted or substituted with one or more chloro or methyl groups;in presence of an alkali iodide and a base to obtain a compound offormula 3,

wherein R₉ is C₁₋₄alkyl wherein the alkyl group is unsubstituted orsubstituted with chloro or methyl groups;R′₂, R′_(2a), R₃, R″₄, R₇, Y and the dotted lines ------have the meaningas defined above;b) subjecting the compound of formula 3 to hydrolysis in presence of anacid or a base to obtain a compound of formula 4,

(c) reacting the compound of formula 4 with a compound of formula 5

R₅—OH  Formula 5

wherein, R₅ has the meaning as defined in formula 1, in presence of anC₁₋₃alkyl sulfonyl halide, LiBr and a base to obtain the compound offormula 6;

wherein R₁₀ is hydrogen or methyl;d) converting the compounds of formula 6 to a compound of formula 1 orsalts thereof.

DETAILED DESCRIPTION OF THE INVENTION

Step a, as disclosed above, is a method for preparation of carbamatederivatives of compounds of formula 2 and involves reaction of acompound of formula 2 with an C₁₋₄alkylchloroformate, wherein the alkylgroup is linear or branched and is unsubstituted or substituted with oneor more halogen, in presence of an alkali iodide and a base to obtain acompound of formula 3. A suitable C₁₋₄alkylchloroformate which may beused in the present invention may be, for example, methylchloroformate,ethylchloroformate, α-chloro ethylchloroformate, isobutylchloroformateand the like. Preferably the C₁₋₄alkylchloroformate isethylchloroformate. Suitable alkali iodide for the reaction may be, forexample, sodium iodide or potassium iodide, preferably, sodium iodidemay be used. The base which may be used in the present process may be aheterogenous base selected from alkali or alkali earth metal hydroxides,carbonates or bicarbonates. A suitable alkali carbonate may be sodiumcarbonate, sodium carbonate, potassium carbonate or lithium carbonate.Preferably, the base used in lithium carbonate.

In a preferred embodiment, the C₁₋₄alkylchloroformate, the base and thealkali iodide compounds may be used in a molar ratio of about 1:3:5.

The reaction may be carried out in presence of an organic solvent. Theorganic solvent which may be used for the reaction may be selected froman inert solvent or a polar aprotic solvent. An inert solvent for thereaction may be an aromatic hydrocarbon solvent such as toluene, xyleneetc. A polar aprotic solvent for the said reaction may be halogenatedsolvents chlorobenzene, ethylene dichloride, methylene dichloride andthe like.

The compounds of formula 2, wherein one or more hydroxy groups areprotected with suitable protecting groups, may be prepared from thecorresponding hydroxy precursors. Such reactions for protecting oxygenradical, are well known in the art. The suitable oxygen protectinggroups for the process of the present invention are, for example, acyl,benzyl, naphthylmethyl, t-butyl, silyl, preferably acyl, more preferablyacetyl. The hydroxyl precursors of compounds of formula 2 may be firstreacted with a suitable protecting group to obtain a compound of formula2 with protected hydroxyl groups, which may then be subjected tosubsequent reaction as disclosed herein in step a. The compound offormula 3 formed in step a may be subjected to step b without furtherpurification.

Step b involves hydrolysis of the carbamate derivative formed in step aabove to obtain the N-demethylated derivative. The step involveshydrolysis of compound of formula 3, to obtain a compound of formula 4.The hydrolysis reaction can be carried out using acidic or basicreagents generally known in the art such as hydrochloric acid, potassiumhydroxide, sulfuric acid etc. Basic hydrolysis is carried out,preferably using potassium hydroxide in presence of polar solvents suchas ethylene glycol or diethylene glycol, more preferably, diethyleneglycol. For acidic hydrolysis, strongly acidic conditions are used,particularly, 5 to 10N sulphuric acid. Preferably, mixture of sulfuricacid and acetic acid is used, such that the less degradation productsare formed. The hydrolysis of the carbamate is accompanied by theremoval of the oxygen protecting group.

Step c as disclosed above, involves N-alkylation of a compound offormula 4, using a compound of formula 5 in presence of C₁₋₃alkyl oraryl sulfonyl chloride, an alkali metal halide and a base. TheC₁₋₃alkylsulfonyl chloride may be selected from methanesulfonylchloride, ethanesulfonyl chloride or propane sulfonylchloride. Arylsulfonyl halide may be selected from benzene sulfonylchloride,p-toluenesulfonylchloride. More preferably the C₁₋₃alkyl or arylsulfonylchloride is methane sulfonyl chloride. The alkali metal halide,may be selected from sodium bromide, potassium bromide, lithium bromideetc. Preferably, the alkali metal halide is lithium bromide. A suitablebase for the reaction may be selected from organic base such astriethylamine, diisopropylamine, triethylamine being preferred. Thereaction may be carried out in an organic polar aprotic solvents ormixtures thereof. The polar aprotic solvent may be selected fromdimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidine(NMP), sulfolane, tetrahydrofuran etc. More preferably the solvent isdimethylformamide.

Step d involves converting the N-alkylated compounds of formula 6 tocompounds of formula 1 or salts thereof. Depending on the final compoundof formula-I sought to be prepared and the compound of formula 6obtained, this step may involve reactions as cited hereinafter.According to one embodiment of process of the present invention, thecompounds of formula 6, wherein R₁₀ is methyl, step d may involveO-demethylation to obtain a compound of formula 1. O-demethylation ofthe morphinane derivative may be carried out using an alkali metalalkoxide and an C₁₋₄alkyl or arylthiol in a suitable solvent. The alkalimetal alkoxide may be selected from sodium alkoxides, such as sodiumt-butoxide, sodium methoxide, sodium ethoxide; or potassium alkoxidessuch as potassium t-butoxide, potassium methoxide, potassium ethoxide,and the like. Preferably the alkali metal alkoxide is potassiumt-butoxide The C₁₋₄alkyl thiols for the reaction may be, for example,propanethiol, methionine, butylthiol, t-butylthiol. The arylthiol may beselected from thiophenol, 1-naphthalenthiol, 2-naphthalenethiol etc.Preferably the aryl thiol is thiophenol. The reaction can be carried outin polar organic solvents like DMF, DMSO, NMP(1-methyl-2-pyrrolidinone), DMA (N,N-dimethylacetamide), DEF(N,N-diethylformamide), DEA (N,N-diethylacetamide), HMPA (hexamethylphosphoramide), DMPU(1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone) and DMEU(1,3-dimethyl-2-imidazolidinone). Preferably the reaction is carried outin DMSO or NMP. More preferably the reaction is carried out in DMSO. Thereaction may be advantageously carried out at a temperature below 200°C., preferably at a temperature ranging from 100 to 150° C., morepreferably at about 130° C. The O-alkylated morphinane derivatives canbe optionally converted to salts thereof.

The compounds of formula 1, wherein R₂ and R₃ together with the carbonatom to which they are attached may form a group of the formula B, maybe prepared from a compound of formula 6, by a process described in U.S.Pat. No. 4,816,586 (referred to as '586 hereinafter) which isincorporated herein as a reference.

The compounds of formula 1, wherein R₂ is hydroxy and R_(2a) ishydrogen, may be prepared from compound of formula 6 wherein R₂ andR_(2a) is oxo by subjecting such a compound of formula 6 using asuitable metal hydride reagent as disclosed in British patent No.1119270 (referred to as '270), which is incorporated herein as areference. Likewise, compounds of formula 1, wherein R₂ and R_(2a)represent methylidene can be prepared from compound of formula 6according to a process disclosed in British Patent No. 1411129 (referredto as '129 hereinafter), which is incorporated herein as a reference.

For compounds of formula 6, wherein R₁₀ is hydrogen, step d may involveconverting the compounds of formula 6 to their salts.

The salts of compounds of formula 1 can be prepared according to theconventional process for preparation of salts. Since the compound offormula I possess a basic nitrogen group in its structure, it can formacid addition salts. The acid salts may be mineral acid salts (e.g.hydrochloride, hydrobromide, sulfate), organic acid salts (e.g. citratesuccinate, maleate, fumarate, malate, tartarate, myristate, pamoate,etc.) and sulfonates (e.g. methanesulfonates, benzenesulfonates,toluensulfonates) and other salts which are customarily employed inpharmaceutical filed in connection with the nitrogen-containingcompounds.

In a preferred embodiment, the present invention relates to process ofpreparing compound of formula 1, represented by compound of formula 1a

wherein,R₁ is hydrogen;R₂ is selected from hydroxy or methoxy;R₃ is selected from hydrogen or a group of the formula A

wherein R₈ is selected from methyl or t-butyl;R₅ is selected from C₃₋₈ alkyl, alkenyl, alkynyl, cycloalkylalkyl,arylalkyl, alkoxyalkyl.the dotted lines ------ indicate an optional single bond;

In another preferred embodiment, the compound of formula 1 isrepresented by compound of formula 1b

wherein,R₁ and R₃ are hydrogen;R₂ and R_(2a) are independently selected from hydrogen, hydroxyl ormethoxy;or R₂ and R_(2a) together represent ═O or ═CH₂;or R₂ and R₃ together may form together with the carbon atoms to whichthey are attached a group of the formula B,

R₄ is selected from hydrogen, hydroxy;

R₅ is selected from C₃₋₈ alkyl, alkenyl, alkynyl, cycloalkylalkyl,arylalkyl, alkoxyalkyl; the dotted lines ------ indicate an optionalsingle bond.

with a proviso that when R₂ and R_(2a) together represent ═O, R₂ and R₃together with the carbon atoms to which they are attached, cannot form agroup of formula B

The compound of formula 2, used in step a above is known in the art.According to a preferred embodiment, the present invention relates to animproved process of preparation of a compound of formula 2, representedby compounds of formula 2a,

wherein R₃ is a group of the formula

wherein R₈ is selected from methyl or t-butyl. The compounds of formula2a may be prepared by a process as outlined in scheme 3 below.

The process comprises of the following steps 1 to 3:

Step 1 involves reacting thebaine with methylvinyl ketone to obtain acompound of formula 8

The reaction is an example of Diels-Alder reaction which is generallywell known in the art. In a preferred embodiment the reaction may becarried out using thebaine and methylvinylketone in a ratio of about1:4. The reaction can be performed by refluxing the two reactants in asuitable solvent. The suitable solvent for the reaction may be selectedfrom isopropyl alcohol, methanol, ethanol, toluene and mixtures thereof.Alternatively, the reaction may be advantageously carried out in absenceof a solvent.

Step 2 of the process, may be optional and involves hydrogenation of theendoetheno compound obtained in step 1 above to obtain endoethanobridged compounds of formula 9. Step 2 is optional and is carried outonly in compounds of formula 2a wherein the 6- and 14-position arelinked by an endoethano bridge. Hydrogenation may be carried out using acatalytic hydrogenating process at atmospheric pressure to obtain acompound of formula 9, possessing a saturated endoethano bridge. Asuitable metal catalyst may be used for the process. The metal catalystmay be, for example, Pd, Pt or Raney Nickel. The reaction may be carriedout in presence of a polar organic solvent or mixtures thereof. Thesolvent may be selected from organic acids such as glacial acetic acidor formic acid or a mixture of these, alcohols preferably methanol,ethanol, isopropyl alcohol, n-butanol or a mixture of these. Morepreferably the reaction is carried out in glacial acetic acid. In apreferred embodiment, the hydrogenation can be carried out atatmospheric pressure.

Step 3 involves reacting the product of step 1 or step 2, i.e. thecompound of formula 8 or 9 with a grignard reagent, R₈MgX⁻, wherein X⁻,represents a halide radical to obtain a compound of formula 2a above.The grignard reagent may be prepared by combining magnesium with thedesired alkyl halide and iodine in a suitable organic solvent ormixtures thereof, under moisture free conditions, in an inertatmosphere. Such a process for preparation of grignard reagent is wellknown in the art. A solution of compound of formula 8 or 9 in a suitablesolvent as mentioned herein below may be added to the thus preparedgrignard reagent to obtain a compound of formula 2a.

The reaction may be carried out in presence of a suitable organicsolvent or mixtures thereof. The suitable organic solvent may beselected from tetrahydrofuran, dioxane, diisopropyl ether, di-tertiarybutyl ether or diethylether.

Surprisingly, it was found by us that the concentration oftetrahydrofuran in diethylether determines the yield as well as thequality of the product obtained. It was observed that use of about 1-15%of tetrahydrofuran in ether improved the yield and the quality of thealkylated product. Accordingly, in one of the preferred embodiment, thegrignard reaction is carried out in presence of diethylether containingabout 1-15% of tetrahydrofuran, more preferably, the solvent isdiethylether containing about 6-10% of THF.

The compounds of formula 2a thus formed may be subjected to a series ofreactions involving N-demethylation to obtain the compounds of formula4, N-alkylation to obtain a compound of formula 6, and/orO-demethylation as described in steps a to d above, in detail.Alternatively, the compounds of formula 2a may be subjected toO-demethylation first, by following a process similar to that describedin step d for compounds of formula 6, wherein R₁₀ is methyl.

In a preferred embodiment, the compound of formula 2a is represented bycompound of formula 2c.

The compound of formula 2c can be prepared by a process as described forformula 2a above. The process comprises the steps of

Step 1 reacting thebaine with methylvinyl ketone to form a compound offormula 8Step 2 hydrogenating compound of formula 8 using catalytic hydrogenationprocess to obtain a compound of formula 9Step 3 reacting a compound 9 with t-butyl magnesium halide in presencemixture of tetrahydrofuran and diethylether to obtain a compound offormula 2c

The compounds of formula 2, as used in step a above, is represented by acompound of formula 2b

may be prepared by a process known in the art. The conventional processinvolves the reacting thebaine, under oxidizing conditions, withperoxide and a per acid to obtain an oxidized product possessing 6-oxosubstitution and a beta oriented hydroxyl group at the 14-position,followed by hydrogenation of the oxidized product to obtain compoundswith a fully saturated ring C and subsequent O-demethylation to obtaincompound of the formula 10

Starting with the compound of formula 10, a number of compounds offormula 2b may be prepared. For example the compound of formula 10 maybe subjected to reduction using a metal hydride reagent to obtaincompounds of formula 2b, wherein R′₂ is hydroxyl and R′_(2a) is hydrogenas disclosed in British Patent No. 1119270, which is incorporated hereinas a reference. Similarly compounds of formula 2b, wherein R′₂ andR′_(2a) together represent ═CH₂, may be prepared from compounds offormula 10, as disclosed in British Patent No. 1411129, which isincorporated herein as a reference. The compounds of formula 2b, whereinR₂ and R₃ together may form, together with the carbon atoms to whichthey are attached a group of the formula B

may be prepared from compounds of formula 10 by a process as disclosedin U.S. Pat. No. 4,816,586, which is incorporated herein as a reference.

The compounds of formula 10 which possess free hydroxy groups aresusceptible to further reactions and thus needs to be suitablyprotected. The suitable hydroxy protecting groups may be, for example,acyl, benzyl, naphthylmethyl, t-butyl, silyl, preferably acyl, morepreferably acetyl. This reaction may be carried out by a process wellknown in the art, for example, treatment with acetic anhydride, whichmay be carried out in absence of a solvent or in presence of a solvent,for example, in toluene, in anhydrous conditions.

In a preferred embodiment, the present invention relates to process ofpreparing compounds of formula I represented by buprenorphine,naltrexone, nalbuphine, naloxone, nalorphine, nalmefene, naltrindole,cyprenorphine, diprenorphine or semorphone. All the above namedcompounds are well known opiate drugs which are useful for treatment fortreatment of one more of conditions selected from pain, drug addiction,drug overdose, alcoholism etc. in humans or veterinary animals.

In a still preferred embodiment of the present invention, the compoundof formula 1 is represented by buprenorphine, represented by formula 1c

According to present invention, the process for preparation ofbuprenorphine comprises the steps of

(a) reacting a compound of formula 2c

with ethylchloroformate in presence of an alkali iodide and Lithiumcarbonate to yield a compound of formula 3c:

(b) subjecting the compound of formula 3c to hydrolysis in presence ofpotassium hydroxide to obtain a compound of formula 4c

(c) reacting the compound of formula 4c with a compound of formula 5c,

in presence of methanesulfonyl chloride and LiBr, to obtain a compoundof formula 6c:

d) converting the compound of formula 6c to a compound of formula 1c orsalt thereof by reacting with potassium tert-butoxide in presence of anC₁₋₄alkyl or arylthiol and optionally reacting with a mineral acid.

Some of the other morphinane derivatives namely cyprenorphine,diprenorphine may be prepared in a manner similar to buprenorphine.

In another preferred embodiment of the present invention, the compoundof formula I is represented by naltrexone, represented by formula 1d

wherein the process comprises the steps of(a) reacting a compound of formula 2d

with ethylchloroformate in presence of an alkali iodide and lithiumcarbonate to obtain a compound of formula 3d;

(b) subjecting the compound of formula 3d to hydrolysis in presence ofan acid to obtain a compound of formula 4d

(c) reacting the compound of formula 4d with a compound of formula 5c

in presence of methane sulphonyl chloride and LiBr, to obtain a compoundof formula 1d.d) converting the compound of formula 1d to its salt.

The other morphinane derivatives namely nalbuphine, nalorphine,nalmefene, naltrindole, may be prepared in a manner similar tonaltrexone.

In yet another preferred embodiment of the present invention, thecompound of formula 1 is represented by Naloxone, represented by formula1e

wherein the process comprises the steps of(a) reacting a compound of formula 2d

with ethylchloroformate in presence of an alkali iodide and lithiumcarbonate to obtain a compound of formula 3d:

(b) subjecting the compound of formula 3d to hydrolysis in presence ofan acid to obtain a compound of formula 4d

(c) reacting the compound of formula 4d with a compound of formula 5e

in presence of methane sulphonyl chloride and LiBr, to obtain a compoundof formula 1e:d) converting the compound of formula 1e to its salt.

The Following examples further illustrate the present invention. Itshould be understood however that the invention is not limited solely tothe particular examples given below.

Example 1 Preparation of Buprenorphine Step 1: Preparation of7-Acetyl-6,14-endo-ethano-6,7,8,14-tetrahydrothebaine

Thebaine (20 Kg) was added to methyl vinylketone (22 L) at roomtemperature and the reaction mixture was heated at 80-90° C. for 3.0hrs. After completion of the reaction, excess methyl vinylketone wasdistilled out under vacuum at a temperature below 60° C., furtherco-distilled with methanol (20 L×2) and finally the product wascollected from the distillation flask by treatment with methanol (40 L)at 0-5° C., filtering and drying the residue obtained. Yield: 22.0 Kg

Step 2: Preparation of7-Acetyl-6,14-endoethano-6,7,8,14-tetrahydrothebaine

7-Acetyl-6,14-endoetheno-6,7,8,14-tetrahydrothebaine (18.5 Kg) (preparedin the step 1, example 1 above) was dissolved in 10% acetic acidsolution (111 L) at 40-45° C., charcoalised and 5% Pd/C (1.387 Kg, 50%wet) was charged to it. Hydrogen gas was purged at 25-30° C. and thereaction was maintained at 25-30° C. for 5-6 hrs. After reactioncompletion, Pd/C was filtered out and the residue was washed with 10%acetic acid solution (37 L) and made alkaline (pH 9.0-10.0) usingaqueous ammonia. The product was extracted with MDC (55.5 L×1, 18.5 L×1)and the combined organic layer was washed with DM Water (18.5 L×1). MDCwas distilled out and the traces of MDC was co-distilled using methanol(18.5 L). The Product was leached by treatment with Methanol (55.5 L)and filtered Yield: 15.4 Kg

Step 3: Preparation of7α-(2-hydroxy-3,3-dimethyl-2-butyl)-6,14-endo-ethano-6,7,8,14-tetrahydrothebaine

(a) Preparation of the t-Butyl Magnesium Chloride

Mg (3.8 Kg) was heated at 90-95° C. for 2.0 Hrs, Iodine (10.0 gm) andTHF (14 L) was added to it. The reaction mixture was cooled to atemperature less than 40° C. and a lot of t-butylchloride (4.0 L) wasadded to it. The reaction mixture was stirred and a solution oft-butylchloride (24 L) in diethyl ether (180 L) was added to thereaction mixture over 4.0-5.0 hrs. The reaction mixture was maintainedunder stirring for 12-14 hrs at 25-30° C.

(b) 7-Acetyl-6,14-endo-ethano-6,7,8,14-tetrahydrothebaine (6.0 Kg) wasadded to t-butyl magnesium chloride in THF and ether as prepared in step(a) above, between 10-15° C. and stirred for 2.0 Hrs. The reaction masswas quenched in solution of ammonium chloride (40.2 Kg) in DM water (120L) and the ether layer was separated. The aqueous layer was extractedwith ether (90 L×2) and the combined organic layer was washed with DMwater (120 L). The organic solvent was distilled out and product wasisolated from the distillation flask by treatment with methanol,filtration and drying the residue obtained. Yield: 5.22 Kg

Step 4: Preparation of7α-(2-hydroxy-3,3-dimethyl-2-butyl)-6,14-endo-ethano-6,7,8,14-tetrahydronorthebaine

(a) A Mixture of7α-(2-hydroxy-3,3-dimethyl-2-butyl)-6,14-endo-ethano-6,7,8,14-tetrahydrothebaine(10 Kg), ethylchlorformate (58.3 L), sodium iodide (16.64 Kg) andlithium carbonate (5.0 Kg) in chlorobenzene (56 L) was heated at 95-105°C. for 14 hrs. After completion of the reaction, the reaction mixturewas diluted with toluene (60 L). The inorganic solid was filtered outand washed with Toluene (60 L). ethylchloroformate, chlorobenzene andtoluene was distilled out under vacuum and the residue degassed to givecrude carbamate compound.

(b) Diethylene glycol (54 L) and Potassium hydroxide (31.4 Kg) wereadded to the degassed carbamate compound obtained in step (a0 above andheated at 130-140° C. for 3.0 hrs. After the completion of the reaction,the reaction mixture was cooled to below 30° C. and DM water (400 L) wasadded to it. The reaction vessel was further cooled to 0-5° C. and thesolid product obtained was filtered, washed with DM water and dried.Yield: 9.02 Kg

Step 5: Preparation ofN-cyclopropylmethyl-7α-(2-hydroxy-3,3-dimethyl-2-butyl)-6,14-endo-ethano-6,7,8,14-tetrahydronorthebaine

Methanesulphonyl chloride (5.31 L) was added to a mixture of cyclopropylmethanol (5.71 L) and triethylamine (20.13 L) in DMF (30.9 Ll) at atemperature of 0-5° C. The solution was maintained 3.0 hrs at 0-5° C.Lithium bromide (6.22 Kg) was added to the reaction mixture at 0-15° C.and maintained at this temperature for 3.0 hrs.7α-(2-hydroxy-3,3-dimethyl-2-butyl)-6,14-endo-ethano-6,7,8,14-tetrahydronorthebaine(6.18 Kg) was added to above reaction mixture at 0-5° C. and thetemperature was raised to 65-70° C. over a period of 1.0 hr. thereaction mixture was maintained at 65-70° C. for 14-15 hrs. Aftercompletion of the reaction, the reaction was quenched in DM Water (124L) at a temperature below 20° C. The aqueous solution was basifies to apH>9.0 and the product was extracted with toluene (62 L×1, 31 L×2) atmore than 9.0 pH. The combined toluene layer was washed with DM water(31 L) followed by 10% Brine Solution (31 L) and concentrated to obtainthe solid product which was isolated from the distillation flask bytreatment with methanol (31 L), filtration and drying the residueobtained. Yield=5.84 Kg

Step 6: Preparation of(2S)-2-[(−)-(5R,6R,7R,14S)-9α-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylbutan-2-ol

Potassium tert-butoxide (12 Kg) was added to the solution of thiophenol(9.45 L) in DMSO (22.2 L) over 1.0 to 3.0 hrs at a temperature below 20°C.N-cyclopropylmethyl-7α-(2-hydroxy-3,3-dimethyl-2-butyl)-6,14-endo-ethano-6,7,8,14-tetrahydronorthebaine(7.4 Kg) was added at RT to the solution of potassium ter-butooxide andthiophenol in DMSO and the reaction mixture was heated to a temperatureof 126-132° C. the reaction was maintained at 126-132° C. for 6.0-8.0hrs. After completion of the reaction, it was cooled to below 25° C. anddiluted with DM water (222 L) followed by a solution of citric acid (37Kg) in DM Water (37 L) to obtain pH below 3.5, further dilute H₂O₂solution (˜30%, 5 L) was added to it. The solution was washed withToluene (74 L×3). Further the aqueous layer was basified with aqueousammonia and extracted with ethyl acetate (74 L×3). The solvent wasdistilled out and product was isolated by Methanol (22 L) at 0-5° C. anddried. Yield=4.42 Kg

Step 7—Preparation of Buprenorphine Hydrochloride

Conc. HCl (2.6 L) was added to the filtered solution of buprenorphinebase (9.65 Kg) in acetone (68 L) at below 15° C. to get pH below 2.0 andstirred for 1.0-2.0 hrs. The HCl salt firmed was filtered, washed withacetone and finally leached with filtered DM water (28 L) at 80° C. anddried. Yield=8.42 Kg.

Example 2 Preparation of Naltrexone Step 1: Preparation of4,5α-Epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one

50 kg thebaine was added to a solution of formic acid (145 kg)maintained at a temperature below 15° C. the solution was heated to 25°C. and maintained at this temperature for 1.0 hr. the reaction mixturewas cooled to 0-5° C. and 30% H₂O₂ aqueous solution (5.5 kg 100% H₂O₂)was added at 0-5° C. The reaction mixture was maintained at 20-25° C.for 3.0 hrs. After completion of the reaction, it was quenched in 560lit DM water and treated with charcoal. To the filtrate 5% Pd/C (1.5 kg)was added and hydrogen gas purged at 20-25° C. The reaction mixture wasmaintained at 20-25° C. for 4-5 hrs. After reaction completion, thecatalyst was filtered off and the pH of the filtrate was adjusted to9-9.5 with aqueous ammonia. The product was extracted with methylenedichloride and subsequently concentrated to obtain a solid which wasisolated with IPA. Yield: 41.7 kg

Step 2: Preparation of 4,5α-Epoxy-3,14-dihydroxy-17-methylmorphinan-6-one

30 kg of DL-Methionine was added to a solution of methane sulphonic acid(390 kg) maintained at 15-20° C. and stirred for 30 minutes. To thissolution, 4,5α-Epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one (40kg) was added at 20° C. and the reaction mass was heated to 50-55° C.the reaction mixture was maintained at 50-55° C. for 12.0 hrs. Afterreaction completion, it was quenched in a mixture of methanol (400 L)and water (800 L) and the pH of the resultant solution was adjusted to9-9.2 with aqueous ammonia at below 20° C. The product was extractedwith methylene dichloride and concentrated to obtain the product whichwas isolated with cyclohexane. Yield: 33.4 kg

Step 3: preparation of 4,5α-Epoxy-3,14-dihydroxy morphinan-6-one(Noroxymorphone)

A mixture of 4,5α-Epoxy-3,14-dihydroxy-17-methyl morphinan-6-one (32.0kg), toluene (225 L) and acetic acetic anhydride (32 L) were heated to95-100° C. and maintained for 8.0 hrs. After reaction completion, thesolvent was distilled at 60-65° C. under vacuum and acetic anhydridetraces were stripped out with toluene and the residue degassed.Chlorobenzene (290 L), lithium carbonate (23.5 kg), sodium iodide (20.8kg), DM water (3.2 L) and ethylchloroformate (280 L) were added to thedegassed mass and heated to 95-105° C., the reaction was maintained at95-105° C. for 12.0 hrs. After reaction completion, the solids werefiltered and filtrate was concentrated at 70° C. under vacuum and theresidue degassed. To the degassed mass acetic acid (96 L) and 15%aqueous sulphuric acid (480 L) was added and the solution was heated to100-110° C. and maintained at 100-110° C. for 24 hrs. After reactioncompletion, the reaction mass was cooled to 0-5° C. and pH of thesolution was adjusted to ˜4.0 with aqueous ammonia. The aqueous solutionwas washed with MDC and the aqueous layer was separated. The separatedaqueous layer was treated with activated charcoal and filtered. The pHof the filtrate was adjusted to 9-9.5 with aqueous ammonia at below 20°C., the solution was further cooled to 0-5° C. and the product formedwas filtered and dried. Yield: 20.3 kg.

Step 3: Preparation of Naltrexone Base

Methanesulphonyl chloride (76 kg) was added to the mixture ofcyclopropyl methanol (50 kg) and triethylamine (192 L) in DMF (400 L)maintained at 0-5° C., the reaction mixture was maintained at 0-5° C.for 3.0 hrs. Lithium bromide (60 Kg) was added to reaction mixture at0-15° C. and maintained for 10-15 minutes. Noroxymorphone (40 Kg) wasadded to above reaction mixture at 0-5° C. and temperature raised to65-70° C. over 1.0 hr period and maintained for 14-15 hrs. Aftercompletion of reaction it was quenched in ice-water below 20° C. and theproduct was extracted with ethylacetate, The ethylacetate layer wasconcentrated and the product was isolated with MDC and cyclohexanemixture at 10-15° C. Yield=35.3 Kg.

Step 4: Preparation of Naltrexone Hydrochloride

70 kg Naltrexone base is taken in 210 Lit DM water and pH was adjustedto ˜2.0 with Conc.HCl and heated to 70-75° C. to get clear solution,filtered to make particle free and slowly cooled to 2-5° C. in 6-8 hrsperiod, filtered and then dried. The base was generated from filtrate bytreatment with sodium hydroxide and converted to HCl salt by repeatingthe above mentioned process. Yield: 59.8 kg

Comparative Examples Example 3 Preparation of(2S)-2-[17-(ethoxycarbonyl)-4,5α-epoxy-3,6-dimethoxy-6α,14-ethano-14α-morphinan-7α-yl]-3,3-dimethylbutan-2-olwithout using Sodium iodide

A mixture of7α-(2-hydroxy-3,3-dimethyl-2-butyl)-6,14-endo-ethano-6,7,8,14-tetrahydrothebaine(5.0 g), ethylchloroformate (29.15 ml) and lithium carbonate (2.5 g) inchlorobenzene (28 L) was heated at 95-105° C. for 14 hrs. The reactionwas monitored by TLC, only ˜50% of reaction completion was observed.

Example 4 Preparation of3,14-Diacetoxy-4,5α-epoxy-17-ethoxycarbonyl-morphinan-6-one withoutusing Sodium iodide

Mixture of 4,5α-Epoxy-3,14-diacetoxy-17-methyl morphinan-6-one (2.0 g),ethylchloroformate (13.71 ml), lithium carbonate (1.14 g) and DM Water(0.16 ml) in chlorobenzene (14.3 ml) was heated at 95-105° C. for 12hrs. About ˜50% of the reaction product was formed as found by TLC.

1-20. (canceled)
 21. A process for preparation of buprenorphine,represented by formula 1c

wherein the process comprises the steps of (a) reacting a compound offormula 2c

with ethylchloroformate in presence of an alkali iodide and Lithiumcarbonate to yield a compound of formula 3c:

(b) subjecting the compound of formula 3c to hydrolysis in presence ofpotassium hydroxide to obtain a compound of formula 4c

(c) reacting the compound of formula 4c with a compound of formula 5c

in presence of methanesulfonyl chloride and LiBr, to obtain a compoundof formula 6c,

d) converting the compound of formula 6c to a compound of formula 1c orsalt thereof by reacting with potassium tert-butoxide in presence of anC₁₋₄alkyl or an arylthiol and optionally reacting with a mineral acid.22. The process as claimed in claim 21, wherein the alkali iodide issodium iodide.
 23. The process as claimed in claim 21, wherein theC₁₋₄alkylchloroformate, base and alkali iodide are used in a ratio of1:3:5.
 24. The process as claimed in claim 21, wherein step d is carriedout at a temperature below 200° C.
 25. The process as claimed in claim21, wherein the reaction is carried out at a temperature between100-150° C.
 26. The process according to claim 21, for preparingcompound of formula 2c,

which comprises the steps of: (a) reacting thebaine with methylvinylketone to form a compound of formula 8

(b) hydrogenating the compound of formula 8 using catalytichydrogenation process to obtain a compound of formula 9,

(c) reacting a compound of formula 9 with t-butylmagnesium chloride inpresence mixture of tetrahydrofuran and diethylether to obtain acompound of formula 2c.
 27. A process according to claim 26, wherein theconcentration of tetrahydrofuran in ether is about 1-15%.
 28. A processaccording to claim 26, wherein the concentration of tetrahydrofuran inether is about 6-10%.
 29. A process according to claim 26, whereinthebaine and methylvinylketone are used in a molar ratio of about 1:4.30. A process as claimed in claim 26, wherein step a is carried out inabsence of a solvent.
 31. A process according to claim 26, whereinhydrogenation is carried out at atmospheric pressure.
 32. A processaccording to claim 26, wherein hydrogenation is carried out in presenceof acetic acid as solvent.